Spinal administration of mu-opioids such as morphine has been widely used in pain management. However, pruritus is reported to be the most common side effect, which sometimes is severe and may lessen the value of spinal opioids for pain relief. A variety of therapeutic agents have been proposed as antipruritics, but they are effective with variable success. Compared with the literature on pain research, there is a deficiency of itch research related to spinal opioids. This may be due, in part, to lack of reliable animal models. Recently, a new experimental itch model was developed in rhesus monkeys. Intrathecal administration of morphine dose-dependently induces long- lasting scratching behavior in monkeys, and this closely parallels clinical observations. This non-human primate model provides a valuable opportunity to study potential treatment and mechanisms of morphine-induced pruritus. The studies proposed in this project will test the central hypothesis that central mu opioid receptors (vs. kappa and delta receptors) mediate opioid-induced pruritus, and that activation of kappa opioid receptors will cause an antipruritic effect. In the proposed studies, scratching activity will be monitored by video recorders and quantified by observers blind to experimental conditions. The potential attenuation of scratching activity by a rationally selected group of opioid receptor agonists and antagonists will be studied following intrathecal morphine injection. The dose-response curve, time course of each agent, and possible side effects will be thoroughly investigated. These studies would provide a systematic understanding of the pharmacology of intrathecal morphine-induced pruritus in primates and establish the basis for identifying potential therapeutically effective antipruritics.